Two challenging cases of anti-MDA-5 dermatomyositis with rapidly progressive interstitial lung disease

Abstract Anti-MDA-5 dermatomyositis (DM) is a subtype of idiopathic inflammatory myopathy, commonly presenting as clinically amyopathic dermatomyositis. It is associated with rapidly progressive interstitial lung disease and a poor prognosis. Here, we present two cases of anti-MDA-5 DM and discuss the challenges associated with timely diagnosis, and the importance of early and aggressive treatment.

This report summarises two cases of anti-MDA-5 DM, presenting in short succession to a district general hospital.Throughout the report, we will discuss the challenges associated with timely diagnosis and the importance of prompt treatment.

Case A
A 47 year-old female of Egyptian heritage with no medical history, presented to acute medicine.She reported three weeks of erythema of her fingers, and a maculopapular rash overlying her elbows and thighs.She also described a 10-day history of early morning stiffness with joint pain and swelling, and respiratory symptoms, including dry cough and shortness of breath on exertion.
On examination, she had mechanic's hands, peri-ungual erythema, Gottron's papules and a diffuse violaceous rash on the lateral aspect of her thighs (Fig. 1).There was clinically evident arthritis affecting her wrists, knees, ankles and small joints of the fingers.Power was 5/5 in all limb movements.Results and management are summarised in Table 1.
Creatine kinase (CK) and inf lammatory markers were normal.A CT thorax-abdomen-pelvis (TAP) revealed no underlying malignancy and MRI thighs showed no evidence of myositis.PET-CT demonstrated a symmetrical inf lammatory polyarthropathy and features of an organising pneumonia.A skin biopsy from the thigh revealed subtle non-specific chronic inf lammatory changes, and direct immunof luorescence was negative for IgG, IgM, IgA and C3.A systemic autoimmune condition was suspected, and over the ensuing month, she received methotrexate (15 mg weekly) and corticosteroids (oral prednisolone with a dose ranging between 30 mg to 60 mg and a single intravenous (IV) dose of methylprednisolone 500 mg) for treatment of the inf lammatory arthritis, whilst awaiting the results from the MSA panel.
Six weeks after presentation, she attended the Emergency Department (ED) due to progressive respiratory symptoms and was discharged with clarithromycin for suspected communityacquired pneumonia.She re-presented two days later and was found to be in type 1 respiratory failure (T1RF).She was    Sats 93% on 10 L supplemental oxygen.Diffuse bibasal crepitations.
Commenced on IV Clarithromycin 500 mg BD and IV Teicoplanin 800 mg OD.Dose of prednisolone doubled to 60 mg.
Transferred to ICU for respiratory support.Strong positive anti-MDA-5 and Ro-52 positivity was later confirmed using myositis immunoblot.She died 2 months later, due to respiratory failure and progressive treatment-resistant pneumomediastinum.

Case B
A 60 year-old female of Chinese heritage and no past medical history, presented to ophthalmology with left eyelid swelling and was diagnosed with pre-septal cellulitis.Six weeks later, she presented to ED with fatigue, reduced mobility and 10 kg unintentional weight loss.Examination revealed cachexia and ulcerating lesions on her shoulders and hips, thought to be pressure sores.Initial investigations showed normocytic anaemia, hypoalbuminaemia and raised C Reactive Protein (CRP) (Table 2).Malignancy was suspected and she was admitted for investigations.A CT TAP showed patches of consolidation, nodularity and ground-glass changes in both lungs, with no evidence of malignancy (Fig. 2).
Fasciculations were noted in her tongue and upper limbs, with normal power on initial assessment.A diagnosis of myositis was supported by an elevated CK (1098 U/L), myopathic changes on electromyography (EMG) and MRI lower limbs demonstrating diffuse oedema.
Non-specific erythema and scale on the face and dorsal aspects of the hands and fingers were noted, raising suspicion for Gottron's papules.Skin biopsy from an erythematous papule on the right third metacarpophalangeal joint showed epidermal basal vacuolation with colloid bodies, and vascular endothelial swelling with fibrinoid necrosis and neutrophilic migration into the vessel wall.Direct immunof luorescence showed linear basement membrane staining with IgA, and positive staining of vessel walls with IgM and C3.The features were suggestive of an immune vasculitic process, which was not felt to be classical for DM.She later developed skin ulceration on the left elbow, mechanic's hands, and nailfold microhaemorrhages.
On day 11, she desaturated and was commenced on piperacillintazobactam for presumed hospital-acquired-pneumonia.Four days later, she was transferred to ICU for the management of severe T1RF.A repeat CT thorax showed worsening ground-glass changes, bilateral consolidation and moderate effusions (Fig. 4).
Given her skin changes, investigations consistent with myositis and rapidly progressive respiratory failure, anti-MDA-5 DM was suspected.She was referred to a tertiary centre for ECMO and aggressive immunosuppression, including IV methylprednisolone (two 1 g pulses followed by weaning doses of oral prednisolone), tofacitinib 5 mg twice daily, tacrolimus (dose guided by levels), three pulses of IV cyclophosphamide (2 doses 500 mg) and IV rituximab (2 doses of 1 g).
Immunology confirmed strong positive anti-MDA-5 and Ro-52 autoantibodies on myositis immunoblot.She died five weeks after admission.

Discussion
Anti-MDA-5 DM is a multi-system condition that can present with cutaneous, muscular, articular and respiratory involvement.Cutaneous features include classical DM signs; the heliotrope sign, shawl sign, Gottron's papules and mechanic's hands, which may not always be present.Deep painful skin ulcers and palmar papules (also known as inverse Gottron's papules) are more specific to anti-MDA-5 DM 5 .Histology of DM skin typically shows an interface dermatitis, and in the MDA-5 subtype there may be epidermal necrosis and vasculopathy 5 , but the findings can be non-specific.Both of our patients presented with cutaneous stigmata of DM.Patient A had Gottron's papules, mechanics hands and nailfold changes, whilst the rash on her thighs likely represented the Holster sign.Patient B presented with deep skin ulcerations, initially misdiagnosed as pressure sores, and with periorbital oedema, thought to be pre-septal 'cellulitis.
ILD is a common manifestation of anti-MDA-5 DM, occurring in 82%-100% of East-Asian cohorts, and 38%-73% of Caucasian patients [6].It is vital to identify RP-ILD promptly, due to its associated mortality rates, which are estimated to be greater than 50% [6].The diagnosis of RP-ILD can be challenging and in both of our cases, it was initially misdiagnosed as infection and/or f luid overload.Unfortunately, due to the aggressive nature of anti-MDA-5 DM, both patients died from respiratory failure.
General Practitioners and General Medicine Physicians must be aware of the clinical features of DM, including skin rashes, for swift onwards rheumatology referral.Early and routine testing for MSAs is vital in the diagnostic work-up of DM and MSA subtypes characterise distinct clinical phenotypes including risk for ILD and cancer [7].When anti-MDA-5 antibodies are detected, clinicians should be alert to the risk of RP-ILD and promptly request appropriate investigations, including HRCT and lung function testing.
Anti-MDA-5 DM is a complex and heterogenous condition, with varied clinical presentations and outcomes.A French cohort study of 83 patients identified three distinct clinical phenotypes of anti-MDA-5 DM [7].In similarity to our cases, the first subgroup corresponded to patients with a high prevalence of RP-ILD and a poor prognosis.In some of these patients, a hyperinf lammatory state with persistent fevers and hyperferritinaemia was seen [3].The second subgroup included patients with predominant skin and muscle involvement and a good prognosis.The final subgroup included those with severe skin vasculopathy and clinical myositis.These patients were predominantly male and had an intermediate prognosis.
Given the clinical heterogeneity of anti-MDA-5 DM, it is important to identify those at risk of rapid disease progression, who should be targeted for early aggressive immunomodulatory therapies.Predictors of poor prognosis and a higher risk of mortality include clinical factors such as older age, male gender, persistent fevers and oxygen desaturations [8], and laboratory features including elevated ferritin, CRP, lactate dehydrogenase and lymphopenia [3].Some studies suggest that the co-existence of anti-Ro-52 antibodies is higher in patients with anti-MDA-5 DM and RP-ILD [9].
In conclusion, we present two cases of anti-MDA-5 DM with RP-ILD.These cases highlight the challenges associated with diagnosis, due to heterogeneity in clinical presentation, and the potential for rapid respiratory deterioration.

Figure 1 .
Figure 1.Images of the skin and CT changes seen in case A (a) Right hand digits showing periungual swelling and erythema (b) Gottron's papules on the right second and third metacarpophalangeal joints.Rough and cracked skin can be seen on the lateral aspect on the thumb, consistent with mechanic's hands.(c) Right lateral thigh showing a diffuse erythematous rash, in keeping with the Holster sign.(d) CT imaging on initial presentation showing mild left lower lobe subpleural consolidation and right lower lobe patchy consolidation (e) Interval CT imaging 6 weeks later showing rapidly progressive ground-glass changes and pneumomediastinum.

Figure 2 .
Figure 2. Images of the skin and CT changes seen in case B (a) Dorsum of the hands showing erythematous scaly papules on the metacarpophalangeal joints, consistent with Gottron's papules (b) Anterior view of the face with mild erythema and scale in the periorbital regions and anterior scalp, with subtle purplish discolouration on the eyelids, in keeping with heliotrope rash.(c) CT imaging on initial presentation showing consolidation in both lungs with scattered nodularity and ground-glass changes (d) Interval CT imaging one week later showing rapidly progressive ground-glass changes with 'crazy paving' pattern and extensive bilateral consolidation.

Table
Table demonstrating timeline of events throughout diagnosis and management of case A

Table 2 .
Table demonstrating timeline of events throughout diagnosis and management of case B